This hypothesis is supported by the observations that pregnancy and breastfeeding reduce the risk of both sporadic and BRCA1-associated breast cancer, and that treatment with the placental hormone hCG confers a similar degree of protection in experimental models. Because the lifetime breast cancer risk of BRCA1 mutation carriers is increased by 85%, tumors arise in them at a significantly lower age than sporadic cancers, and in addition they are unresponsive to endocrine and immunotherapy due to their negativity for estrogen receptor alpha (ERa), progesterone receptor (PR), and Her2, factors that worsen their prognosis, this high risk population is an ideal target for implementing preventive measures based on the use of r-hCG as a chemopreventive agent. This approach is supported by our demonstration that the complete differentiation of the breast induced by pregnancy is one of the main mechanisms that confer protection to both women and rodents, in which treatment of virgin rats with hCG prevents the initiation and progression of chemically induced mammary cancer. Furthermore, we have demonstrated that the differentiation of the breast imprints a specific genomic signature that is characteristic of parous women and could serve therefore as a biomarker indicative of the lifetime decreased breast cancer risk. In this exploratory application we are aiming at establishing the proof of principle that treatment of "high breast cancer risk" women with recombinant human chorionic gonadotropin (r-hCG) will change their breast epithelium's high risk genomic profile to one similar to that identified in women with a history of early full first term pregnancy. For this purpose, breast epithelial cells will be collected by random periareolar fine needle aspiration (RPFNA) from 18 women carriers of BRCA1 deleterious mutations. Cells will be cytopathologically evaluated; RNA will be extracted for analysis of gene expression by cDNA microarray, and immunocytochemical determination of cell proliferation by Ki67, ER and PR status, parameters that will serve as a baseline of the "high risk" genomic profile. We propose to test whether a 90 day (3-month) treatment with r-hCG will activate or downregulate genes related to immune surveillance, DNA repair, programmed cell death, transcription, and chromatin structure/activators/co activators in comparison with the pre-treatment genomic profile, changes that will indicate that the "high risk" has been converted to a "low risk" risk genomic signature, such as that found in women with a history of early first full term pregnancy. This knowledge will serve as the basis for establishing novel genomic signatures as intermediate biomarkers for larger preventive clinical trials at the completion of this project. [unreadable] [unreadable] [unreadable]